Darbepoietin-Alfa after High-Dose Melphalan and Autologous Hemopoietic Progenitor Cell in Multiple Myeloma Patients: A Pilot Study

Massimo Martino, Ida Callea, Tiziana Moscato, Antonella Pontari, Elisa Spiniello, Roberta Fedele

Department of Oncology and Hematology, Azienda Ospedaliera BMM, Reggio Calabria, Italy.

DOI: 10.4236/ojbd.2012.23012                

Abstract

We describe the effects of Darbepoietin-alfa (Darbe) administration in Multiple Myeloma (MM) after autologous he-mopoietic progenitor cell transplantation (AHPCT). 26 MM patients undergoing AHPCT entered this study. 34 hemo-globin (Hb)-matched patients who had not received recombinant human erythropoietin (Epo) or Darbe and were treated with the same protocol were retrospectively selected for comparative data. Darbe (150 micro g total dose/weekly) was initiating in four weeks after AHPCT, with the aim of achieving an Hb level of ≥11 g/dl. The time to response to Darbe therapy was longer in the patients with Hb < 10 g/dL (p = 0.05) and with endogenous Epo levels ≤ 50 mU/ml (p = 0.0098). Hb level on day 60 and 90 after AHPCT, was faster for Darbe recipients (12.5, range 9.4 - 15.4, vs 10.6, range 8.8 - 13.4 g/dL, p = 0.0001, and 13.5, range 12.3 - 14.3, vs 12, range 9.8 - 14 g/dL, respectively, p = 0.0001). The need for Red Blood Cells transfusion, included in the period of 30 - 90 days post- AHPCT was similar (p = ns). This study demonstrates the accelerating effect of Darbe on Hb increase in the setting evaluated and shows that this effect signify- cantly depends on the endogenous Epo level at the start of treatment. The strategy of giving Darbe around 1 month after high-dose melphalan (HDM) doesn’t reduce RBC transfusion requirement.

Keywords

Darbepoietin-Alfa; Anemia; Multiple Myeloma; Autologous Hematopoietic Progenitor Cell Transplanta-tion

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	T. J. Littlewood, “Erythropoietin for the Treatment of Anaemia Associated with Hematological Malignancy,” Hematological Oncology, Vol. 19, No. 1, 2001, pp. 19-30. doi:10.1002/hon.663
[2]	A. Osterborg, “Recombinant Human Erythropoietin (rHuEPO) Therapy in Patients with Cancer-Related Anaemia: What Have We Learned?” Medical Oncology, Vol. 15, Suppl. 1, 1998, pp. S47-S49.
[3]	G. D. Demetri, M. Kris, J. Wade, L. Degos and D. Cella, “Quality-of-Life Benefit in Chemotherapy Patients Treated with Epoetin Alfa Is Independent of Disease Response or Tumor type: Results from a Prospective Community Oncology Study,” Journal of Clinical Oncology, Vol. 16, No. 10, 1998, pp. 3412-3425.
[4]	T. J. Littlewood, E. Bajetta, J. W. Nortier, E. Vercammen, B. Rapoport and Epoetin Alfa Study Group, “Effects of Epoetin Alfa on Hematologic Parameters and Quality of Life in Cancer Patients Receiving Non-Platinum Chemotherapy: Results of a Randomised, Double-Blind, Placebo-Controlled Trial,” Journal of Clinical Oncology, Vol. 19, No. 11, 2001, pp. 2865-2874.
[5]	J. L. Gabrilove, C. S. Cleeland, R. B. Livingston, B. Sarokhan, E. Winer and L. H. Einhorn, “Clinical Evaluation of Once-Weekly Dosing of Epoetin Alfa in Chemotherapy Patients: Improvements in Hemoglobin and Quality of Life Are Similar to Three-Times-Weekly Dosing,” Journal of Clinical Oncology, Vol. 19, No. 11, 2001, pp. 2875-2882.
[6]	J. Glaspy, R. Bukowski, D. Steinberg, C. Taylor, S. Tchekmedyian and S. Vadhan-Raj, “Impact of Therapy with Epoetin Alfa on Clinical Outcomes in Patients with Nonmyeloid Malignancies during Cancer Chemotherapy in Community Oncology Practice. Procrit Study Group,” Journal of Clinical Oncology, Vol. 15, No. 3, 1997, pp. 1218-1234.
[7]	R. A. Kyle, “Multiple Myeloma: Review of 869 Cases,” Mayo Clinic Proceedings, Vol. 50, No. 1, 1975, pp. 29-40.
[8]	F. Dammacco, G. Castaldi and S. R?djer, “Efficacy of Epoetin Alfa in the Treatment of Anemia of Multiple Myeloma,” British Journal of Haematology, Vol. 113, No. 1, 2001, pp. 172-179. doi:10.1046/j.1365-2141.2001.02715.x
[9]	A. Osterborg, Y. Brandberg, V. Molostova, G. Iosava, K. Abdulkadyrov, M. Hedenus, D. Messinger and Epoetin Beta Hematology Study Group, “Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human Erythropoietin, Epoetin Beta, in Hematologic Malignancies,” Journal of Clinical Oncology, Vol. 20, No. 10, 2002, pp. 2486-2494. doi:10.1200/JCO.2002.08.131
[10]	J. L. Steegmann, J. López, M. J. Otero, M. L. Lamana, R. de la Cámara, M. Berberana, A. Díaz and J. M. Fernández-Ra?ada, “Erythropoietin Treatment in Allogeneic BMT Accelerates Erythroid Reconstitution: Results of a Prospective Controlled Randomised Trial,” Bone Marrow Transplantation, Vol. 10, No. 6, 1992, pp. 541546.
[11]	S. Klaesson, O. Ringdén, P. Ljungman, B. L?nnqvist and L. Wennberg, “Reduced Blood Transfusions Requirement after Allogeneic Bone Marrow Transplantation: Results of a Randomised, Double-Bind Study with High-Dose Erythropoietin,” Bone Marrow Transplantation, Vol. 13, No. 4, 1994, pp. 397-402.
[12]	C. B. Mille and H. M. Lazarus, “Erythropoietin in Stem Cell Transplantation,” Bone Marrow Transplantation, Vol. 27, No. 10, 2001, pp. 1011-1016. doi:10.1038/sj.bmt.1703022
[13]	D. H. Henry, “Epoetin Alfa and High-Dose Chemotherapy,” Seminars in Oncology, Vol. 25, No. 3, Suppl. 7, 1998, pp. 54-57.
[14]	M. Danova and S. Ferreri, “Anemia and Epoetin Alfa in High-Dose Chemotherapy Programs for Breast Cancer Patients,” Seminars in Oncology, Vol. 29, No. 3, Suppl. 8, 2002, pp. 21-25.
[15]	B. Barlogie, S. Jagannath, K. R. Desikan, S. Mattox, D. Vesole, D. Siegel, G. Tricot, N. Munshi, A. Fassas, S. Singhal, J. Mehta, E. Anaissie, D. Dhodapkar, S. Naucke, J. Cromer, J. Sawyer, J. Epstein, D. Spoon, D. Ayers, B. Cheson and J. Crowley, “Total Therapy with Tandem Transplants for Newly Diagnosed Multiple Myeloma,” Blood, Vol. 93, No. 1, 1999, pp. 55-65.
[16]	M. Tribalto, S. Amadori, L. Cudillo, T. Caravita, G. Del Poeta, G. Meloni, G. Avvisati, M. T. Petrucci, A. Pulsoni, G. Leone, S. Sica, M. Martelli, A. Tabilio, G. Fioritoni, I. Majolino and F. Mandelli, “Autologous Peripheral Blood Stem Cell Transplantation as First Line Treatment of Multiple Myeloma: An Italian Multicenter Study,” Haematologica, Vol. 85, No. 1, 2000, pp. 52-58.
[17]	M. Attal, J. L. Harousseau, A. M. Stoppa, J. J. Sotto, J. G. Fuzibet, J. F. Rossi, P. Casassus, H. Maisonneuve, T. Facon, N. Ifrah, C. Payen and R. Bataille, “A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple Myeloma. The Intergroupe Fran?ais du Myélome,” The New England Journal of Medicine, Vol. 335, No. 2, 1996, pp. 91-97. doi:10.1056/NEJM199607113350204
[18]	P. Moreau, T. Facon, M. Attal, C. Hulin, M. Michallet, F. Maloisel, J.-J. Sotto, F. Guilhot, G. Marit, C. Doyen, J. Jaubert, J.-G. Fuzibet, S. Fran?ois, L. Benboubker, M. Monconduit, L. Voillat, M. Macro, C. Berthou, V. Dorvaux, B. Pignon, B. Rio, T. Matthes, P. Casassus, D. Caillot, N. Najman, B. Grosbois, R. Bataille and J.-L. Harousseau for the Intergroupe Francophone du Myélome, “Comparison of 200 mg/m2 Melphalan and 8 Gy Total Body Irradiation Plus 140 mg/m2 Melphalan as Conditioning Regimens for Perip
[19]	B. Barlogie, S. Jagannath, D. H. Vesole, S. Naucke, B. Cheson, S. Mattox, D. Bracy, S. Salmon, J. Jacobson, J. Crowley and G. Tricot, “Superiority of Tandem Autologous Transplantation over Standard Therapy for Previously Untreated Multiple Myeloma,” Blood, Vol. 89, No. 3, 1997, pp. 789-793.
[20]	M. Attal, J.-L. Harousseau, T. Facon, F. Guilhot, C. Doyen, J.-G. Fuzibet, M. Monconduit, C. Hulin, D. Caillot, R. Bouabdallah, L. Voillat, J.-J. Sotto, B. Grosbois and R. Bataille for the InterGroupe Francophone du Myélome, “Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma,” The New England Journal of Medicine, Vol. 349, No. 26, 2003, pp. 24952502. doi:10.1056/NEJMoa032290
[21]	A. Osterborg, “New Erythropoietic Proteins: Rationale and Clinical Data,” Seminars in Oncology, Vol. 31, No. 3, Suppl. 8, 2004, pp. 12-18. doi:10.1053/j.seminoncol.2004.04.005
[22]	M. Bloomfield, G. Jaresko, J. Zarek and N. Dozier, “Guidelines for Using Darbepoetin Alfa in Patients with Chemotherapy-Induced Anemia,” Pharmacotherapy, Vol. 23, No. 12, Pt. 2, 2003, pp. 110S-118S. doi:10.1592/phco.23.16.110S.31970
[23]	J. Patton, T. Reeves and J. Wallace, “Effectiveness of Darbepoetin Alfa versus Epoetin Alfa in Patients with Chemotherapy-Induced Anemia Treated in Clinical Practice,” Oncologist, Vol. 9, No. 4, 2004, pp. 451-458.
[24]	M. Martino, F. Morabito, G. Messina, G. Irrera, G. Pucci and P. Iacopino, “Fractionated Infusions of Cryopreserved Stem Cells May Prevent DMSO-Induced Major Cardiac Complications in Graft Recipients,” Haematologica, Vol. 81, No. 1, 1996, pp. 59-61.
[25]	L. Ponchio, A. Zambelli, A. De Stefano, F. S. R. D. Cuna, C. Perotti and P. Pedrazzoli, “Transfusion Requirement Can Be Abolished by Epoietin-A and Autologous Platelet Predeposit in Patients Receiving High Dose Chemotherapy with Stem Cell Support,” Haematologica, Vol. 85, No. 2, 2000, pp. 219-220.
[26]	F. Baron, P. Frère, G. Fillet and Y. Beguin, “Tandem High-Dose Therapy (HDT) for Multiple Myeloma: Recombinant Human Erythropoietin Therapy Given between First and Second HDT Allows Second Peripheral Blood Stem Cell Transplantation without Red Blood Cell Transfusion,” British Journal of Haematology, Vol. 123, No. 1, 2003, pp. 103-105. doi:10.1046/j.1365-2141.2003.04556.x
[27]	J. D. Rizzo, M. R. Somerfield, K. L. Hagerty, J. Seidenfeld, J. Bohlius, C. L. Bennett, D. F. Cella, B. Djulbegovic, M. J. Goode, A. A. Jakubowski, M. U. Rarick, D. H. Regan, A. E. Lichtin, American Society of Clinical Oncology and American Society of Hematology, “Use of Epoetin and Darbepoetin in Patients with Cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update,” Journal of Clinical Oncology, Vol. 26, No. 1, 2008, pp. 132-149. doi:10.1200/JCO
[28]	C. Bokemeyer, M. S. Aapro, A. Courdi, J. Foubert, H. A. Link, A. Osterborg, L. Repetto and P. Soubeyran, “EORTC Guidelines for the Use of Erythropoietic Proteins in Anaemic Patients with Cancer,” European Journal of Cancer, Vol. 40, 2004, pp. 2201-2216. doi:10.1016/j.ejca.2004.07.015
[29]	J. Crawford, D. Cella, C. S. Cleeland, P. Y. Cremieux, G. D. Demetri, B. J. Sarokhan, M. B. Slavin and J. A. Glaspy, “Relationship between Changes in Hemoglobin Level and Quality of Life during Chemotherapy in Anemic Cancer Patients Receiving Epoetin Alfa Therapy,” Cancer, Vol. 95, No. 4, 2002, pp. 888-895. doi:10.1002/cncr.10763
[30]	G. Vanstraelen, F. Baron, P. Frère, K. Hafraoui, G. Fillet and Y. Beguin, “Efficacy of Recombinant Human Erythropoietin Therapy Started One Month after Autologous Peripheral Blood Stem Cell Transplantation,” Haematologica, Vol. 90, No. 9, 2005, pp. 1269-1270.
[31]	J. Glaspy, D. Henry, R. Patel, S. Tchekmedyian, S. Applebaum, D. Berdeaux, R. Lloyd, R. Berg, M. Austin, G. Rossi and Darbepoetin Alfa 20010162 Study Group, “Effects of Chemotherapy on Endogenous Erythropoietin Levels and the Pharmacokinetics and Erythropoietic Response of Darbepoetin Alfa: A Randomised Clinical Trial of Synchronous versus Asynchronous Dosing of Darbepoetin Alfa,” European Journal of Cancer, Vol. 41, No. 8, 2005, pp. 1140-1149. doi:10.1016/j.ejca.2005.01.021
[32]	A. Pedrazzini, “Erythropoietin and GM-CSF following Autologous Bone Marrow Transplantation,” European Journal of Cancer, Vol. 29A, Suppl. 2, 1993, pp. S15-S17. doi:10.1016/S0959-8049(05)80284-9
[33]	R. Pene, F. R Appelbaum, L. Fisher, K. Lilleby, J. Nemunaitis, R. Storb and C. D. Buckner, “Use of Granulocyte-Macrophage Colony-Stimulating Factor and Erythropoietin in Combination after Autologous Marrow Transplantation,” Bone Marrow Transplantation, Vol. 11, No. 3, 1993, pp. 219-222.
[34]	L. J. Ayash, A. Elias, M. Hunt, G. Demetri, C. Wheeler, I. Tepler, G. Schwartz, R. Mazanet, E. Reich, M. McCauley, et al., “Recombinant Human Erythropoietin for the Treatment of the Anaemia Associated with Autologous Bone Marrow Transplantation,” British Journal of Haematology, Vol. 87, No. 1, 1994, pp. 153-161. doi:10.1111/j.1365-2141.1994.tb04886.x
[35]	H. Link, M. A. Boogaerts, A. A. Fauser, S. Slavin, J. Reiffers, N. C. Gorin, A. M. Carella, F. Mandelli, S. Burdach, A. Ferrant, et al., “A Controlled Trial of Recombinant Human Erythropoietin after Bone Marrow Transplantation,” Blood, Vol. 84, No. 10, 1994, pp. 33273335.
[36]	F. Locatelli, M. Zecca, P. Pedrazzoli, L. Prete, S. Quaglini, P. Comoli, P. De Stefano, Y. Beguin, G. Robustelli della Cuna, F. Severi, “Use of Recombinant Human Erythropoietin after Bone Marrow Transplantation in Pediatric Patients with Acute Leukemia: Effect on Erythroid Repopulation in Autologous versus Allogeneic Transplants,” Bone Marrow Transplantation, Vol. 13, No. 4, 1994, pp. 403-410.
[37]	N. J. Chao, J. R. Schriber, G. D. Long, R. S. Negrin, M. Catolico, B. W. Brown, L. Miller and K. G. Blume, “A Randomized Study of Erythropoietin and Granulocyte Colony-Stimulating Factor (G-CSF) versus Placebo and G-CSF for Patients with Hodgkin’s and Non-Hodgkin’s Lymphoma Undergoing Autologous Bone Marrow Transplantation,” Blood, Vol. 83, No. 10, 1994, pp. 2823-2828.
[38]	C. B. Miller and S. Mills, “Erythropoietin after Bone Marrow Transplantation,” Hematology/Oncology Clinics of North America, Vol. 8, No. 5, 1994, pp. 975-992.
[39]	L. Pierelli, G. Scambia, G. Menichella, G. D’Onofrio, G. Salerno, P. B. Panici, M. L. Foddai, M. Vittori, M. Lai, M. Ciarli, G. Puglia, S. Mancuso and B. Bizzi, “The Combination of Erythropoietin and Granulocyte Colony-Stimulating Factor Increases the Rate of Haemopoietic Recovery with Clinical Benefit after Peripheral Blood Progenitor Cell Transplantation,” British Journal of Haematology, Vol. 92, No. 2, 1996, pp. 287-294. doi:10.1046/j.1365-2141.1996.d01-1502.x
[40]	A. M. Vannucchi, A. Bosi, A. Ieri, S. Guidi, R. Saccardi, L. Lombardini, S. Linari, D. Laszlo, G. Longo and P. Rossi-Ferrini, “Combination Therapy with G-CSF and Erythropoietin after Autologous Bone Marrow Transplantation for Lymphoid Malignancies: A Randomized Trial,” Bone Marrow Transplantation, Vol. 17, No. 4, 1996, pp. 527-531.
[41]	P. Benedetti, L. Pierelli, G. Scambia, M. L. Foddai, M. G. Salerno, G. Menichella, M. Vittori, F. Maneschi, U. Caracussi, R. Serafini, G. Leone and S. Mancuso, “HighDose Carboplatin, Etoposide and Melphalan (CEM) with Peripheral Blood Progenitor Cell Support as Late Intensification for High-Risk Cancer: Non-Haematological, Haematological Toxicities and Role of Growth Factor Administration,” British Journal of Cancer, Vol. 75, No. 8, 1997, pp. 1205-1212. doi:10.1038/bjc.1997.206
[42]	Y. Beguin, G. K. Clemons, R. Oris and G. Fillet, “Circulating Erythropoietin Levels after Bone Marrow Transplantation: Inappropriate Response to Anemia in Allogeneic Transplants,” Blood, Vol. 77, No. 4, 1991, pp. 868873.
[43]	Y. Beguin, R. Oris and G. Fillet, “Dynamics of Erythropoietic Recovery Following Bone Marrow Transplantation: Role of Marrow Proliferative Capacity and Erythropoietin Production in Autologous versus Allogeneic Transplants,” Bone Marrow Transplantation, Vol. 11, No. 4, 1993, pp. 285-292.
[44]	F. Baron, G. Fillet and Y. Beguin, “Erythropoiesis after Nonmyeloablative Stem-Cell Transplantation Is Not Impaired by Inadequate Erythropoietin Production as Observed after Conventional Allogeneic Transplantation,” Transplantation, Vol. 74, No. 12, 2002, pp. 1692-1696. doi:10.1097/00007890-200212270-00008
[45]	Y. Beguin, F. Baron and G. Fillet, “Influence of Marrow Activity on Serum Erythropoietin Levels after Autologous Hematopoietic Stem Cell Transplantation,” Haematologica, Vol. 83, No. 12, 1998, pp. 1076-1081.
[46]	F. Baron, P. Frère, G. Fillet and Y. Beguin, “Recombinant Human Erythropoietin Therapy Is Very Effective after an Autologous Peripheral Blood Stem Cell Transplant When Started Soon after Engraftment,” Clinical Cancer Research, Vol. 15, No. 88, 2003, pp. 5566-5572.